Abstract Cancer therapies targeting a specific signaling pathway (targeted therapy) in a specific tumor (personalized therapy) are the current ?state-of-the-art?, while treatment and management for advanced cancer remain the barrier to overall cancer treatment success. One common feature of advanced cancer is frequent genetic inactivation of pRb and p53, the two major tumor suppressors. Finding effective treatments for these cancers depends on finding antitumor mechanisms that remain effective when both pRb and p53 are genetically inactivated. We have succeeded in blocking pRb and p53 doubly deficient tumorigenesis in mouse tumor models by deleting Skp2. We now propose to use pRb and p53 doubly deficient prostate tumorigenesis in mice to model metastatic castration resistant prostate cancer (mCRPC) in patients to identify new treatment for this lethal cancer. The advance in TCGA of prostate cancer has documented statistically significant co- occurrences of RB1 and TP53 in mCRPC, providing the rationale for our proposed studies. The emerging cancer organoids system has established a resource of six mCRPC organoid lines and we have established mouse prostate tumor organoids to translate our mouse model findings to human mCRPC side-by-side on the organoid platform. In this application, we propose to determine the potential of targeting the Skp2/Cks1 pocket to inhibit mouse DKO prostate tumorigenesis and translate the findings to human mCRPC on organoid platform followed by metastasis assay with organoid cells in immune compromised mice (Specific Aim 1), and to determine mechanism and role of Skp2 function in promoting Warburg effects in DKO prostate tumorigenesis and determine the effects of inhibiting LDHA and Skp2/Cks1 pocket in combination in mouse DKO prostate tumorigenesis and translate the finding to human mCRPC in organoids and in metastasis assays (Specific Aim 2).